Single-cell RNA profiling of blood CD4⁺ T cells identifies distinct helper and dysfunctional regulatory clusters in...

To characterize the complexity of the CD4⁺ T cell compartment in patients with systemic lupus erythematosus (SLE), we performed single-cell RNA sequencing of sorted blood CD4⁺ T cells from pediatric patients and healthy donors. We identified naive, memory, regulatory T (T_reg) cell, proliferative and interferon-stimulated gene-high (ISG-high) clusters. Within the memory compartment, both follicular and peripheral helper cells were expanded in patients with lupus nephritis and/or high disease activity. Cytotoxic signatures were enriched in effector memory T cells re-expressing CD45RA (TEMRA), as well as in two memory subclusters, one of which overlapped with T helper 10-like cells (T_H10). Notably, we observed an expansion of dysfunctional T_reg cells in patients with lupus nephritis, along with upregulation of TLR5 and FCRL3 in SLE-naive T_reg cells, suggesting a potential link with mucosal microbial dysbiosis. These findings highlight distinct CD4⁺ T cell subsets that may contribute to aberrant antibody responses and impaired immune regulation in SLE.